IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59155-w.html
   My bibliography  Save this article

Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes

Author

Listed:
  • Hongru Li

    (Nanjing Medical University)

  • Jingyi Zhao

    (Nanjing Medical University)

  • Jinglan Dai

    (Nanjing Medical University)

  • Dongfang You

    (Nanjing Medical University
    Nanjing Medical University)

  • Yang Zhao

    (Nanjing Medical University
    Key Laboratory of Biomedical Big Data of Nanjing Medical University)

  • David C. Christiani

    (Harvard University
    Harvard Medical School)

  • Feng Chen

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • Sipeng Shen

    (Nanjing Medical University
    Key Laboratory of Biomedical Big Data of Nanjing Medical University
    Nanjing Medical University)

Abstract

C-reactive protein (CRP) serves as a pivotal marker of systemic inflammation, yet its genetic architecture has predominantly been explored within European populations. Our multi-ancestry sequencing-based genome-wide association study (seqGWAS) meta-analysis encompasses 447,369 Europeans, 10,389 Africans, 9685 Asians, and 9200 Hispanics in the discovery set, and 23,521 Europeans, 7160 Africans, 771 Asians, and 5178 Hispanics in the replication set. We identify 113 independent association signals (Pdiscovery ≤ 5 × 10−9 and Preplication ≤ 0.05), including 21 loci that passed the conditional analysis, among which 3 are European-specific. Cross ancestry fine-mapping pinpoints 19 of 113 independent signals within the 95% credible set. Functional annotation reveals significant enrichment in blood tissue, H3K27me3 histone marks, and exonic regions. Leveraging the Polygenic Priority Score (PoPS) and gene-based analyses, we implicate 151 genes as potential regulators of CRP levels, 55 of which have not been previously reported. Among these, 17 genes and four proteins show causal evidence or strong colocalization with CRP-related pathologies.

Suggested Citation

  • Hongru Li & Jingyi Zhao & Jinglan Dai & Dongfang You & Yang Zhao & David C. Christiani & Feng Chen & Sipeng Shen, 2025. "Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59155-w
    DOI: 10.1038/s41467-025-59155-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59155-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-59155-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Cristopher V. Van Hout & Ioanna Tachmazidou & Joshua D. Backman & Joshua D. Hoffman & Daren Liu & Ashutosh K. Pandey & Claudia Gonzaga-Jauregui & Shareef Khalid & Bin Ye & Nilanjana Banerjee & Alexand, 2020. "Exome sequencing and characterization of 49,960 individuals in the UK Biobank," Nature, Nature, vol. 586(7831), pages 749-756, October.
    2. Nikhil B. Ghate & Sungmin Kim & Yonghwan Shin & Jinman Kim & Michael Doche & Scott Valena & Alan Situ & Sangnam Kim & Suhn K. Rhie & Heinz-Josef Lenz & Tobias S. Ulmer & Shannon M. Mumenthaler & Wooji, 2023. "Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Benjamin B. Sun & Joshua Chiou & Matthew Traylor & Christian Benner & Yi-Hsiang Hsu & Tom G. Richardson & Praveen Surendran & Anubha Mahajan & Chloe Robins & Steven G. Vasquez-Grinnell & Liping Hou & , 2023. "Plasma proteomic associations with genetics and health in the UK Biobank," Nature, Nature, vol. 622(7982), pages 329-338, October.
    4. Saredo Said & Raha Pazoki & Ville Karhunen & Urmo Võsa & Symen Ligthart & Barbara Bodinier & Fotios Koskeridis & Paul Welsh & Behrooz Z. Alizadeh & Daniel I. Chasman & Naveed Sattar & Marc Chadeau-Hya, 2022. "Genetic analysis of over half a million people characterises C-reactive protein loci," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    6. Jason Flannick & Josep M. Mercader & Christian Fuchsberger & Miriam S. Udler & Anubha Mahajan & Jennifer Wessel & Tanya M. Teslovich & Lizz Caulkins & Ryan Koesterer & Francisco Barajas-Olmos & Thomas, 2019. "Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls," Nature, Nature, vol. 570(7759), pages 71-76, June.
    7. Mitja I. Kurki & Juha Karjalainen & Priit Palta & Timo P. Sipilä & Kati Kristiansson & Kati M. Donner & Mary P. Reeve & Hannele Laivuori & Mervi Aavikko & Mari A. Kaunisto & Anu Loukola & Elisa Lahtel, 2023. "Author Correction: FinnGen provides genetic insights from a well-phenotyped isolated population," Nature, Nature, vol. 615(7952), pages 19-19, March.
    8. Liu Yang & Ya-Nan Ou & Bang-Sheng Wu & Wei-Shi Liu & Yue-Ting Deng & Xiao-Yu He & Yi-Lin Chen & Jujiao Kang & Chen-Jie Fei & Ying Zhu & Lan Tan & Qiang Dong & Jianfeng Feng & Wei Cheng & Jin-Tai Yu, 2024. "Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Gao Wang & Abhishek Sarkar & Peter Carbonetto & Matthew Stephens, 2020. "A simple new approach to variable selection in regression, with application to genetic fine mapping," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1273-1300, December.
    10. Saredo Said & Raha Pazoki & Ville Karhunen & Urmo Võsa & Symen Ligthart & Barbara Bodinier & Fotios Koskeridis & Paul Welsh & Behrooz Z. Alizadeh & Daniel I. Chasman & Naveed Sattar & Marc Chadeau-Hya, 2022. "Author Correction: Genetic analysis of over half a million people characterises C-reactive protein loci," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    11. Daniel Taliun & Daniel N. Harris & Michael D. Kessler & Jedidiah Carlson & Zachary A. Szpiech & Raul Torres & Sarah A. Gagliano Taliun & André Corvelo & Stephanie M. Gogarten & Hyun Min Kang & Achille, 2021. "Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program," Nature, Nature, vol. 590(7845), pages 290-299, February.
    12. Mei-lin Weng & Wan-kun Chen & Xiang-yuan Chen & Hong Lu & Zhi-rong Sun & Qi Yu & Peng-fei Sun & Ya-jun Xu & Min-min Zhu & Nan Jiang & Jin Zhang & Jian-ping Zhang & Yuan-lin Song & Duan Ma & Xiao-ping , 2020. "Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    13. Mitja I. Kurki & Juha Karjalainen & Priit Palta & Timo P. Sipilä & Kati Kristiansson & Kati M. Donner & Mary P. Reeve & Hannele Laivuori & Mervi Aavikko & Mari A. Kaunisto & Anu Loukola & Elisa Lahtel, 2023. "FinnGen provides genetic insights from a well-phenotyped isolated population," Nature, Nature, vol. 613(7944), pages 508-518, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Javier Botey-Bataller & Hedwig D. Vrijmoeth & Jeanine Ursinus & Bart-Jan Kullberg & Cees C. Wijngaard & Hadewych Hofstede & Ahmed Alaswad & Manoj K. Gupta & Lennart M. Roesner & Jochen Huehn & Thomas , 2024. "A comprehensive genetic map of cytokine responses in Lyme borreliosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Ichcha Manipur & Guillermo Reales & Jae Hoon Sul & Myung Kyun Shin & Simonne Longerich & Adrian Cortes & Chris Wallace, 2024. "CoPheScan: phenome-wide association studies accounting for linkage disequilibrium," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Xuening Zhang & Hao Zhao & Meng Wan & Jinyu Man & Tongchao Zhang & Xiaorong Yang & Ming Lu, 2025. "Associations of 2923 plasma proteins with incident inflammatory bowel disease in a prospective cohort study and genetic analysis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    4. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Jujiao Kang & Yue-Ting Deng & Bang-Sheng Wu & Wei-Shi Liu & Ze-Yu Li & Shitong Xiang & Liu Yang & Jia You & Xiaohong Gong & Tianye Jia & Jin-Tai Yu & Wei Cheng & Jianfeng Feng, 2024. "Whole exome sequencing analysis identifies genes for alcohol consumption," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. Jonathan Mitchell & Niedzica Camacho & Patrick Shea & Konrad H. Stopsack & Vijai Joseph & Oliver S. Burren & Ryan S. Dhindsa & Abhishek Nag & Jacob E. Berchuck & Amanda O’Neill & Ali Abbasi & Anthony , 2025. "Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    8. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Linda Ottensmann & Rubina Tabassum & Sanni E. Ruotsalainen & Mathias J. Gerl & Christian Klose & Elisabeth Widén & Kai Simons & Samuli Ripatti & Matti Pirinen, 2023. "Genome-wide association analysis of plasma lipidome identifies 495 genetic associations," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    11. Dongfang You & Yaqian Wu & Mengyi Lu & Fang Shao & Yingdan Tang & Sisi Liu & Liya Liu & Zewei Zhou & Ruyang Zhang & Sipeng Shen & Theis Lange & Hongyang Xu & Hongxia Ma & Yongmei Yin & Hongbing Shen &, 2025. "A genome-wide cross-trait analysis characterizes the shared genetic architecture between lung and gastrointestinal diseases," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    12. Xiao-Yu He & Bang-Sheng Wu & Liu Yang & Yu Guo & Yue-Ting Deng & Ze-Yu Li & Chen-Jie Fei & Wei-Shi Liu & Yi-Jun Ge & Jujiao Kang & Jianfeng Feng & Wei Cheng & Qiang Dong & Jin-Tai Yu, 2024. "Genetic associations of protein-coding variants in venous thromboembolism," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    13. Anders Mälarstig & Felix Grassmann & Leo Dahl & Marios Dimitriou & Dianna McLeod & Marike Gabrielson & Karl Smith-Byrne & Cecilia E. Thomas & Tzu-Hsuan Huang & Simon K. G. Forsberg & Per Eriksson & Mi, 2023. "Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    14. William R. Reay & Dylan J. Kiltschewskij & Maria A. Biase & Zachary F. Gerring & Kousik Kundu & Praveen Surendran & Laura A. Greco & Erin D. Clarke & Clare E. Collins & Alison M. Mondul & Demetrius Al, 2024. "Genetic influences on circulating retinol and its relationship to human health," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    15. Hui Chen & Zeyang Wang & Lihai Gong & Qixuan Wang & Wenyan Chen & Jia Wang & Xuelian Ma & Ruofan Ding & Xing Li & Xudong Zou & Mireya Plass & Cheng Lian & Ting Ni & Gong-Hong Wei & Wei Li & Lin Deng &, 2024. "A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Shuai Yuan & Jie Chen & Jiawei Geng & Sizheng Steven Zhao & James Yarmolinsky & Elizabeth V. Arkema & Sarah Abramowitz & Michael G. Levin & Kostas K. Tsilidis & Stephen Burgess & Scott M. Damrauer & S, 2025. "GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    17. Sylvia Hartmann & Summaira Yasmeen & Benjamin M. Jacobs & Spiros Denaxas & Munir Pirmohamed & Eric R. Gamazon & Mark J. Caulfield & Harry Hemingway & Maik Pietzner & Claudia Langenberg, 2023. "ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    18. Yash Patel & Jean Shin & Eeva Sliz & Ariana Tang & Aniket Mishra & Rui Xia & Edith Hofer & Hema Sekhar Reddy Rajula & Ruiqi Wang & Frauke Beyer & Katrin Horn & Max Riedl & Jing Yu & Henry Völzke & Rob, 2024. "Genetic risk factors underlying white matter hyperintensities and cortical atrophy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    19. Salim Megat & Christine Marques & Marina Hernán-Godoy & Chantal Sellier & Geoffrey Stuart-Lopez & Sylvie Dirrig-Grosch & Charlotte Gorin & Aurore Brunet & Mathieu Fischer & Céline Keime & Pascal Kessl, 2025. "CREB3 gain of function variants protect against ALS," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    20. Xingjie Hao & Zhonghe Shao & Ning Zhang & Minghui Jiang & Xi Cao & Si Li & Yunlong Guan & Chaolong Wang, 2023. "Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59155-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.